Non-specific accumulation of glycosphingolipids in GNE myopathy

Autor: Marjan Huizing, Katherine Patzel, Erell Le Poëc-Celic, Yongmin Zhang, Heidi Dorward, William A. Gahl, Petcharat Leoyklang, Nikolay V. Kukushkin, Bixue Xu, Matthieu Sollogoub, Tal Yardeni, Terry D. Butters, Yves Blériot, Dominic S. Alonzi
Přispěvatelé: Oxford Glycobiology Institute, University of Oxford [Oxford], National Human Genome Research Institute (NHGRI), National Institutes of Health [Bethesda] (NIH), Sackler School of Medicine, Tel Aviv University [Tel Aviv], Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA), Institut Parisien de Chimie Moléculaire (IPCM), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Glycochimie Organique Biologique et Supramoléculaire (GOBS), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers-Institut de Chimie du CNRS (INC), University of Oxford, Tel Aviv University (TAU), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2013
Předmět:
Zdroj: Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease, 2014, 37 (2), pp.297--308. ⟨10.1007/s10545-013-9655-6⟩
ISSN: 1573-2665
DOI: 10.1007/s10545-013-9655-6⟩
Popis: UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE) is a bifunctional enzyme responsible for the first committed steps in the synthesis of sialic acid, a common terminal monosaccharide in both protein and lipid glycosylation. GNE mutations are responsible for a rare autosomal recessive neuromuscular disorder, GNE myopathy (also called hereditary inclusion body myopathy). The connection between the impairment of sialic acid synthesis and muscle pathology in GNE myopathy remains poorly understood.Glycosphingolipid (GSL) analysis was performed by HPLC in multiple models of GNE myopathy, including patients' fibroblasts and plasma, control fibroblasts with inhibited GNE epimerase activity through a novel imino sugar, and tissues of Gne(M712T/M712T) knock-in mice.Not only neutral GSLs, but also sialylated GSLs, were significantly increased compared to controls in all tested models of GNE myopathy. Treatment of GNE myopathy fibroblasts with N-acetylmannosamine (ManNAc), a sialic acid precursor downstream of GNE epimerase activity, ameliorated the increased total GSL concentrations.GNE myopathy models have increased total GSL concentrations. ManNAc supplementation results in decrease of GSL levels, linking abnormal increase of total GSLs in GNE myopathy to defects in the sialic acid biosynthetic pathway. These data advocate for further exploring GSL concentrations as an informative biomarker, not only for GNE myopathy, but also for other disorders of sialic acid metabolism.
Databáze: OpenAIRE
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